Atherosclerotic vascular disease (ASVD) is the leading cause of death in developed countries. Although there are numerous recognized risk factors for ASVD, including hypertension, hyperlipidemia, diabetes, cigarette smoking, and genetics, approximately one half of all ASVD deaths cannot be attributed to these risk factors. Periodontal disease (PD) is recognized as a risk factor for ASVD independent of other known risk factors, and has been suggested as a cause of ASVD in cases lacking traditional risk factors. PD is a microbial-induced inflammatory disease of the tissues surrounding and supporting the teeth, which can lead to tooth loss. The oral cavity is inhabited by more than 650 species of bacteria, but only a select few are implicated in development of periodontal disease. Four of these select species are Porphyromonas gingivalis (Pg), Treponema denticola (Td), Tanerella forsythia (Tf) and Fusobacterium nucleatum (Fn). Evidence supporting the association between ASVD and PD includes epidemiological studies and detection of components of these four bacteria (as well as of other oral microbes) within human atherosclerotic plaque samples. However, there is not sufficient evidence to declare a causal relationship between PD and ASVD. It is not clear if the bacterial components detected in plaque were from viable bacteria causing active infection, or from dead bacteria caught in plaque as bystanders. Atherosclerosis-prone ApoEnull mice and periodontitis-prone integrin 6-/- mice will be chronically orally infected with Pg+Td+Tf+Fn for 24 weeks, and upon sacrifice will be examined for evidence of periodontal disease, bacteremia and atherosclerosis (Aims 1 and 3). This mouse model is designed to demonstrate successful induction of periodontal disease, natural systemic spread of periodontal pathogens, and induction of plaque formation. Presence of live bacteria in the aortic wall will be detected, and an immune response to the bacteria within the aortic wall and atherosclerotic plaque will be determined (Aim 2). The objective of this study is to demonstrate that periodontal pathogenic bacteria are directly involved in atherosclerosis formation by actively invading vessel walls and exacerbating the innate immune response. Additionally, we will develop the integrin 6-/- mouse as a model of periodontal disease and systemic disease more closely resembling the human diseases. The data from these studies will strengthen the evidence for a direct association between PD and ASVD, and will emphasize the importance of maintaining oral health for overall systemic health.